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A First Glimpse of the Exome in Schizophrenia

14 July 2011. Sequencing the protein-coding parts of the genome, or exome, turns up rare, protein-altering mutations in individuals with schizophrenia not found in controls, according to a study published online July 10, 2011, in Nature Genetics. Guy Rouleau of the University of Montreal and colleagues report that the rate of de-novo mutations—spontaneously occurring events not inherited from parents—was elevated in the exomes of 14 sporadic cases of schizophrenia, and these potentially disrupt genes not previously linked to the disorder.

As the first to report exome sequencing in schizophrenia, the study gives a fine resolution glimpse of the genome not offered by genomewide association studies (GWAS) or copy number variation (CNV) studies (see SRF schizophrenia genetics series). The researchers focused on non-familial cases of schizophrenia, in which parents of an individual with schizophrenia were unaffected by the disorder, and there was no family history of other psychotic disorders or drug abuse. To identify potential genetic contributors to these sporadic cases, they sequenced the exomes of 14 individuals with schizophrenia and both parents so that they could select mutations that were not inherited.

After capturing about 72 percent of the exome and sequencing it, first author Simon Girard and colleagues made comparisons to reference genomes and found plenty of variants. With their interest in sporadic causes of schizophrenia, the researchers homed in on 73 variants occurring only in an individual with schizophrenia—but not found in his or her parents, or in controls consisting of the parents of the other probands. Validation with Sanger sequencing whittled these down to 15 variants, which came from eight of the 14 individuals with schizophrenia. None of these mutations have been previously documented.

Making sense of nonsense and missense
Four of these variants consisted of nonsense mutations, which insert a stop codon to result in a prematurely truncated protein; 11 were missense mutations, changing an amino acid. The authors note that this ratio of nonsense to missense mutations is greater than expected by chance, and suggest it reflects a greater burden of deleterious mutations in schizophrenia.

One nonsense mutation was found in ZNF480, a gene encoding a transcription factor; the second nonsense variant occurred in KPNA1, which encodes a protein indirectly involved in antibody and T cell receptor generation in the immune system. The third occurred in LRP1, which encodes a lipoprotein receptor-related protein that is regulated by amyloid precursor protein, better known for its role in Alzheimer's disease, and the fourth nonsense mutation landed in ALS2CL, a gene encoding a putative modulator of alsin, which is associated with neurodegeneration. Of the 11 missense variants, protein modeling algorithms predicted seven would be deleterious to protein function.

The researchers calculated that these 15 spontaneously occurring variants represented a de-novo mutation rate over twice that calculated for the entire genomes of healthy individuals in the 1000 Genomes Project. This is consistent with the group's previous report of an increased de-novo mutation rate in synaptic genes in schizophrenia and autism (Awadalla et al., 2010), and suggests that these kinds of rare, spontaneously occurring genetic mistakes contribute to schizophrenia.

Though the results offer up some new genes to ponder, they also illustrate the difficulties of linking rare variants to disease: which of these variants are causal, and which are innocent bystanders? As has been argued before when rare CNVs turned up in schizophrenia (see SRF related news story and SRF news story), it is hard to do statistics on rare events, especially when the frequency of these variants in control populations is still largely unknown. Still, this foray into the fine-resolution territory of sequencing is a step toward a fuller understanding of schizophrenia genetics.—Michele Solis.

Reference:
Girard SL, Gauthier J, Noreau A, Xiong L, Zhou S, Jouan L, Dionne-Laporte A, Spiegelman D, Henrion E, Diallo O, Thibodeau P, Bachand I, Bao JY, Tong AH, Lin CH, Millet B, Jaafari N, Joober R, Dion PA, Lok S, Krebs MO, Rouleau GA. Increased exonic de novo mutation rate in individuals with schizophrenia. Nat Genet. 2011 Jul 10. Abstract

 
Comments on News and Primary Papers
Primary Papers: Increased exonic de novo mutation rate in individuals with schizophrenia.

Comment by:  Daniel Weinberger, SRF Advisor
Submitted 14 July 2011 Posted 14 July 2011

The paper by Girard et al. is the first of a number of papers that will soon appear searching for rare single nucleotide DNA sequence variants in patients with schizophrenia. It marches to the popular drumbeat that rare single nucleotide variants, like rare CNVs, represent part of the complex genetic architecture of the population of individuals with the diagnosis of schizophrenia. While this is likely to be true, de-novo variants in particular (i.e., those not inherited) cannot account for the “missing heritability” that has so far not been accounted for by common variant association studies, unless for some improbable reason the genetics of the machinery that leads to DNA replication errors is associated with risk for schizophrenia. The findings of Girard et al.—that there is an increased burden of coding, likely functional, de-novo mutations in individuals with schizophrenia—are based on a very small sample (n = 14 patients). The reference sequence data to which they compare their results are based on even smaller numbers of fully sequenced individuals.

I...  Read more


View all comments by Daniel Weinberger

Primary Papers: Increased exonic de novo mutation rate in individuals with schizophrenia.

Comment by:  Patrick Sullivan, SRF AdvisorJin Szatkiewicz
Submitted 17 August 2011 Posted 19 August 2011

Girard et al. sequenced the exomes of 14 parent-child trios, each comprising an individual with sporadic schizophrenia and his or her unaffected parents. They found 15 de-novo mutations from eight probands, and suggest that individuals with schizophrenia are more likely to have de-novo and deleterious mutations specific to coding sequences. This is the first paper in this area, and the third in neuropsychiatric disorders following mental retardation (Vissers et al., 2010) and sporadic autism spectrum disorders (O'roak et al., 2011).

However, some major issues complicate interpretation of the results reported in Girard et al. and weaken the conclusions the authors wish to draw.

First, regarding sequencing coverage, mutation discovery from exome data is a challenging problem, and identifying de-novo mutations is particularly enriched by technical errors. The authors reported that the exome capture resulted in an average of 72 percent targeted regions covered with read depth...  Read more


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